1. Field of the Invention
The present invention relates to a pharmaceutical composition comprising N-aryl N′ morpholino/piperidino thiocarbamide derivatives for preventing and treating diabetes, diabetic complications, insulin resistance and insulin resistance syndrome.
2. Description of the Related Art
Diabetes mellitus is a severe chronic metabolic abnormality. There were 194 million diabetic patients and more than 300 million people exposed to a risk of developing diabetes around the world in the year 2003. WHO predicted that diabetic population would increase to 333 million by 2025 (Yakup Daily, Aug. 28, 2003). About 90% of diabetic patients have type II diabetes mellitus (World Health Organization, Fact sheet 236, http://www.who.int/inf-fs/en/fact236.html 1999; Accessed Jul. 25, 2002). It is assumed that the annual costs needed for treating diabetic patients aged between 20 and 79 amount to minimum 153 billion dollars. It is expected that this medical expenses will reach from 213 billion to 396 billion dollars at 2025. Considering that enormous medical expenses are spent and many people are exposed to diabetes, the development of drugs for preventing and treating diabetes and diabetic complications is in urgent need.
Type I diabetes mellitus is an immune-mediated disease caused by chronically and selectively destroyed pancreatic β-cells. As a consequence, a destruction of β-cells secreting insulin results in insulin deficiency that leads to hyperglycemia, diabetes, polydipsia and weight loss, and so on. Diabetic complications are loss of eyesight, renal failure, neurological disorders, heart disease, etc.
In case of type II diabetes mellitus, the first shown dysfunction is insulin resistance that insulin-sensitive cells do not respond to insulin of normal level (Consensus Development conference on Insulin Resistance 5-6 Nov. 1997, American Diabetes Association, Diabetes Care, 1998; 21:310-314). Pancreatic β-cells increase insulin secretion in order to overcome such insulin resistance. But, as time passes, β-cell function lowers, consequently insulin secretion decreases, resulting in a hyperglycemia. Type II diabetes mellitus is complexly caused by insulin-mediated suppression dysfunction of hepatic glucose excretion, insulin-mediated glucose uptake disorders into muscle and adipose cells, and β-cell dysfunction (DeFronzo R A, Bonadonna R C, Ferrannini E, Pathogenesis of NIDDM, A balanced overview, Diabetes Care, 1992; 15: 318-368). And, this insulin resistance is an important cause in the development of various metabolic diseases. Insulin resistance indicates that a tissue response to insulin actions decreases, and the resultant symptoms are called insulin resistance syndrome (IRS), syndrome X, metabolic syndrome, plurimetabolic syndrome, new world syndrome, syndrome X+, deadly quartet, or diabesity (Zimmet, P. Addressing the insulin resistance syndrome. A role for the thiazolidinediones, 2002). Insulin resistance is accompanied with insulin-mediated glucose uptake disorders, glucose intolerance, hyperinsulinemia, triglyceride (very low density lipoprotein triglyceride) increase, HDL cholesterol decrease, hypertension, and so on (Reaven, G. M. Banting lecture. Role of insulin resistance in human disease. Diabetes 37, 1595-1607, 1988). Insulin resistance syndrome contains systemic obesity, central obesity, upper abdominal obesity, arteriosclerosis, acanthosis nigricans, polycystic ovarian syndrome, hyperuricemia, PAI-1 (plasminogen activator inhibitor-1) increase, thrombolystic abnormality, endothelial and smooth muscle dysfunction, microalbuminuria, and so on (Peter, P., Nuttall, S. L., Kendall, M. J. Insulin resistance—the new goal!. J. Clinical Pharmacy and Therapeutics 28, 167-174, 2003). According to a recent study, it is suggested that insulin resistance cause the following diseases: sleep apnoea (Punjabi, N. M., Ahmed, M. M., Polotsky, V. Y., Beamer, B. A., O'Donnell, C. P. Sleep-disordered breathing, glucose intolerance, and insulin resistance. Respiratory Physiology & Neurobiology 136, 167-178, 2003); prostate cancer (Barnard, R. J., Aronson, W. J., Tymchuk, C. N., Ngo, T. H. Prostate cancer: another aspect of the insulin-resistance syndrome, Obesity reviews 3, 303-308, 2002); type I diabetes (Greenbaum, C. J. Insulin resistance in type 1 diabetes. Diabetes Metab. Res. Rev. 18, 192-200, 2003); affective disorders (Rasgon, N., Jarvik, L. Insulin resistance, affective disorders, and Alzheimer's disease: review and hypothesis. J. Gerontol. A Biol. Sci. Med. Sci. 59, 178-183, 2004); Alzheimer's disease (Watson, G. S., Craft, S. The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs. 17, 27-45, 2003); stroke (Kernan, W. N., Inzucchi, S. E., Viscoli, C. M., Brass, L. M., Bravata, D. M., Horwits, R. I. Insulin resistance and risk for stroke. Neurology 59, 809-815, 2002); breast cancer (Stoll, B. A. Upper abdominal obesity, insulin resistance and breast cancer risk. Int. J. Obes. Relat. Metab. Disord. 26, 747-753, 2002); inflammation (Perseghin, G., Petersen, K., Shulman, G. I. Cellular mechanism of insulin resistance: potential links with inflammation. Int. J. Obes. Relat. Metab. Disord. 27 Suppl. 3, S6-S11, 2003); rheumatoid arthristis (Dessein, P. H., Joffe, B. I., Stanwix, A. E. Inflammation, insulin resistance, and aberrant lipid metabolism as cardiovascular factors in rheumatoid arthristis. J. Rheumatol. 30, 1403-1405, 2003); etc. Accordingly, a substance capable of preventing and treating insulin resistance can be used as medicament for preventing and treating the above insulin resistance syndrome.
According to a recent study, it is disclosed in many reports that some chemical substances containing morpholine have an effect of improving diabetes and insulin resistance. For example, it is suggested that PPMP (DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol) have an effect on the treatment of TNF-induced insulin resistance (Grigsby, R. J., Dobtowsky, R. T. Inhibition of ceramide production reverses TNF-induced insulin resistance. Biochem. Biophys. Res. Commun. 287, 1121-1124, 2001) and SIN-1 (3-morpholino sydnonimine) be acted as an insulin promoter in a liver (Guarino, M. P., Afonso, R. A., Raimundo, N., Raposo, J. F., Macedo, M. P. Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G588-G594, 2003). In addition, it is suggested that some chemical substances containing a piperidine structure have a blood glucose lowering action (Rynbrandt, R. H., Schmidt, F. L., Szmuszkovicz, J. cis-1-(2-(p-anisidinomethyl)cyclohexyl)piperidine and related compounds. Oral hypoglycemic agents. J. Med. Chem. 14, 985-987; Srivastava, V., Suresh, A. J., Pandeya, S. N., Pandey, A. Evaluation of some acylamide derivatives as potential hypoglycemic agents. Boll. Chim. Farm. 135, 452-457, 1996).